The overall aim of this project is to characterize factors that act on neuronal stem or progenitor cells in the adult and aging brain and influence or regulate endogenous adult neurogenesis. Knowledge about the biology of these processes will be relevant for future therapeutic approaches to Alzheimer's Disease (AD) and other neurodegenerative disorders, in that manipulation of neuronal stem or progenitor cells in situ night allow neuronal replacement and cellular and structural regeneration. The underlying rationale is that identification of regulatory mechanisms under physiological conditions will provide the necessary tools to manipulate neuronal stem or progenitor cells for therapeutic goals. In this project we propose to investigate molecular events and constraints that regulate neurogenesis in the adult and aged rodent and primate dentate molecular events and constraints that regulate neurogenesis in the adult and aged rodent and primary dentate gyrus. Glutamatergic fibers project to the dentate gyrus and damage to these fibers has been reported to influence neurogenesis. We will therefore also investigate in transgenic animals the role of glutamate receptors in neurogenic regulation. The specific objectives of this project are: 1) Determine if and to what extent hippocampal neurogenesis occurs in adult primates. 2) Determine the effects of long-term environmental stimulation on neurogenesis in the aging brain of mice. 3) Determine the role of learning and physical activity as key factors in environmental stimulation of adult hippocampal neurogenesis. 4) Characterize the role of glutamatergic system n the regulation of neurogenesis in the adult and aging hippocampus.